A method for constructing the C2-C12 dispiroacetal moiety of altohyrtin A

Full text of DOI:10.1021/jo9613904

7646
J . Org. Chem. 1996, 61, 7646-7647
Sch em e 1
A Meth od for Con str u ctin g th e C2-C12
Disp ir oa ceta l Moiety of Altoh yr tin A
Michelle M. Claffey and Clayton H. Heathcock*
Department of Chemistry, University of California,
Berkeley, California 94720
Received J uly 23, 1996
Several novel, marine-derived, macrocyclic lactones
with identical or similar skeletal structures, including
the altohyrtins,1,2 the spongistatins,3 and cinachyrolide
A,4 have recently been isolated and shown to be extremely
potent cancer cell growth inhibitors. In screens against
the U.S. National Cancer Institute's 60 human cancer
cell lines, many of these compounds displayed high
cytotoxicity toward a subset of chemoresistant tumor
types. Of these compounds, altohyrtin A (1) is the only
compound for which the absolute stereochemistry has
been reported. In light of the high activity of this
compound in conjunction with its paucity, studies are
being directed toward a total synthesis of 1.
Sch em e 2
dure of Kitamura and Noyori et al.6 in which the hydroxy
ester 6 was obtained in excellent yield and purity (>97%
ee). Both enantiomers of ester 6 are commercially
available, yet very expensive ($40/1 g from Aldrich
Chemical Co., Inc.). Therefore, multigram quantities of
6 were obtained more cost efficiently using the Noyori
protocol. Silyl protection of the secondary hydroxyl as
the tert-butyldiphenylsilyl (TBDPS) ether followed by
careful DIBALH reduction of the ester provided aldehyde
4 in nearly quantitative yield. Condensation of aldehyde
4 with the lithium anion of hydrazone 5 gave the desired
hydrazone product, which was used crude due to insta-
bility. Several hydrazone cleavage conditions were ex-
plored but resulted in unsatisfactory yields of ketone 7,
including sodium periodate7,8 (46%), ozone9,10 (48%), and
silica gel11 (50-60%). The optimum cleavage conditions
were found to be m-CPBA12 in THF at -78 °C, which
provided ketone 7 more conveniently and in a reproduc-
ible two-step yield of 59%. On the basis of spectroscopic
analysis of isolated byproducts, the deprotonation fol-
lowed by â-elimination of aldehyde 4 prior to anion
addition was suspected to be the cause of this moderate
yield. The problem was solved by transmetalation of the
In our research aimed at this target, we were inter-
ested in synthesizing the spiroketal 2, which is a model
for the C2-C12, A-B spiroketal fragment of altohyrtin
A (1). We envisioned spiroketal 2 (Scheme 1) as being
derived from the C2-symmetric diketone 3, which upon
further disconnection revealed the readily-available al-
dehyde 4 and acetone dimethylhydrazone (DMH),5 5, as
possible starting materials. Although spiroketal 2 pos-
sesses the opposite stereochemistry reported for the
corresponding fragment of 1, either enantiomer of alde-
hyde 4 is equally accessible using the same procedure.
The three-step synthesis of the aldehyde 4 (Scheme 2)
began by catalytic, asymmetric hydrogenation of com-
mercially-available methyl acetoacetate using a proce-
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S0022-3263(96)01390-4 CCC: $12.00 © 1996 American Chemical Society

Communications
J . Org. Chem., Vol. 61, No. 22, 1996 7647
Sch em e 3
F igu r e 1. ORTEP representation of the 4-nitrobenzoate
derivative of the methyl-addition product of 11.
to provide silyl enol ether 9 in 96% yield as a 6:1 mixture
of regioisomers. The TIPS enol ether was found to be
superior to the corresponding TBS enol ether, which in
the subsequent steps was prone to decomposition, result-
ing in ring-opening of the spiroketal by cleavage of the
silyl group and â-elimination. Reduction of ketone 9 with
L-Selectride in THF gave the desired axial alcohol 10 in
88% yield. Silyl cleavage with TBAF‚3H2O in THF at
-78 °C unmasked the remaining carbonyl moiety to
afford the hydroxy ketone 11 in 95% yield. Methylcerium
addition to 11 provided the desired tertiary, axial alcohol
in 91% yield. The stereochemistry of this addition was
confirmed by X-ray crystallographic analysis of the
4-nitrobenzoate derivative (Figure 1).15 Selective acyla-
tion of the secondary hydroxyl with acetic anhydride and
DMAP in pyridine completed the synthesis of the spiroket-
al 2 with a 92% yield.
In summary, a synthesis of the desired model (2) has
been accomplished in a 23% overall yield for 13 steps
starting from commercially-available methyl acetoac-
etate. The application of the chemistry developed for the
model to the synthesis of the C2-C12, A-B spiroketal
of altohyrtin A (1) is currently being investigated. The
synthesis of a C2-symmetric intermediate, analogous to
diketone 3, and its subsequent desymmetrization is being
explored. An advantage of this synthesis is that either
enantiomer would be accessible in the event that the
absolute stereochemistry was incorrectly assigned or
should the enantiomer of the A-B spiroketal fragment
exist in any of the other related natural products.
lithium anion with cerium trichloride prior to addition,
which resulted in an improved two-step yield of 80%.
Although cerium anions have been shown to be less basic
than the corresponding lithium anions,13 the generation
of the cerium anion of a hydrazone is to the best of our
knowledge novel.
The remaining carbons of the diketone skeleton were
installed by a second condensation in which the â-hy-
droxy ketone 7 was treated with 2.1 equiv of LDA
followed by the addition of another equivalent of aldehyde
4. Purification of the three diastereomers of ketone 8
was not possible at this point; therefore, the crude
material was deprotected with tetrabutylammonium
fluoride (TBAF) in THF and ketalized by the addition of
48% aqueous HF. Purification of the ketalized diol
mixture was also unsuccessful. However, the silicon
byproducts were removed through extractive procedures,
and the resulting crude diols were oxidized with Dess-
Martin periodinane14 to afford the desired diketone 3 in
a 44% yield over the three steps. Purification of the
diketone 3 resulted in loss of product due to its instablity
to silica gel. The three-step yield could considerably
improve in the application of this chemistry to the
synthesis of the altohyrtin system, since the requisite
compounds would be presumably less polar, potentially
resulting in greater ease of purification.
Transformation of the diketone 3 into the model
spiroketal 2 is shown in Scheme 3. Masking one carbonyl
of the C2-symmetric diketone 3 as a silyl enol ether
allowed for the efficient differentiation of the two
carbonyls. The selective monosilyl enol ether formation
was successfully performed with 1.02 equiv of LDA in
HMPA/THF followed by addition of TIPSCl in hexanes
Ack n ow led gm en t. This work was supported by a
research grant from the United States Public Health
Service (GM 15067).
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and spectral data for all compounds (9 pages).
(13) (a) Imamoto, T. Pure Appl. Chem. 1990, 62, 747-752. (b)
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T.; Tawarayama, Y.; Sugiura, Y.; Mita, T.; Hatanaka, Y.; Yokoyama,
M. J . Org. Chem. 1984, 49, 3904-3912. (d) Imamoto, T.; Sugiura, Y.;
Takiyama, N. Tetrahedron Lett. 1984, 25, 4233-4236. (e) Imamoto,
T.; Kusumoto, T.; Yokoyama, M. Tetrahedron Lett. 1983, 24, 5233-
5236.
J O9613904
(15) The author has deposited atomic coordinates for this structure
with the Cambridge Crystallographic Data Centre. The coordinates
can be obtained, on request, from the Director, Cambridge Crystal-
lographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.
(14) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155-4156.